The Estrogen Receptor Joins Other Cancer Biomarkers as a Predictor of Outcome

Figure 1

Hormone receptors in endometrial tumors. In ER-𝛼 dependent tumors (left side), estrogen induces growth factors and PR through ER-𝛼. This creates a positive feedback loop between ER-𝛼 and growth factor signaling. However, progesterone (P4), when bound to PR, downregulates ER and PR. In addition, MAPK activation downstream of growth factor signaling results in phosphorylation of ER and PR and the ligand-dependent loss of PR and ER proteins by ubiquitination-mediated proteasomal degradation. ER-𝛼 and PR levels are increased again at the level of transcription by estrogen stimulation. Hence, the growth of these tumors is dependent upon estrogen and is limited by progesterone, suggesting that the patient will respond to progestin hormonal therapy. High expression of ER-𝛽, if present, can inhibit the function of ER-𝛼. For GPR30 dependent tumors (right panel), we hypothesize that proliferation is driven by the constitutive activation of one or more components of a growth factor pathway. Growth does not depend upon the presence of estrogen and is not limited by progesterone. Also, the classical steroid hormone receptors are downregulated as a result of constitutive phosphorylation via MAPK. This is predicted because the phosphorylation of the receptors leads to its targeting the proteasome for degradation. By virtue of the constitutive activation of a growth factor pathway, such tumors grow independently of classical hormonal signaling.